DESCRIPTION: The goal of this R21 grant proposal is to test the feasibility of using cannabinoid receptor (CB) agonists as microbicides to prevent HIV infection and transmission. These non-psychoactive derivatives of tetrahydrocannabinol (THC) have a broad range of anti-inflammatory properties and increase the stratification of vaginal tissue in animal models. The compounds to be tested are agonists of CB2, which are found in the immune system and also present in other peripheral tissues, including vaginal tissue. During the R21 project, the effect o these agonists on the: 1) vaginal tissue thickness, tight junctions, gene expression, and barrier function, 2) expression of factors involved in innate immunity, 3) expression of CB2 in epithelial tissues and HIV host cells, 4) migration of HIV infected cells within vaginal tissue, and 5) capture and transfer HIV to CD4+ T cells will be investigated. Successful completion of the R21 work is anticipated to lead to advancement of one of the CB agonists into preclinical/clinical trials for use as a prophylactic HIV treatment or as an HIV microbicide adjuvant.